Abstract

Polyploid giant cancer cells (PGCCs) are abundant in cancers after chemotherapy. PGCCs have generally been considered nonviable because of their inability to execute mitosis. However, our recently reported studies challenged this paradigm by showing that PGCCs were capable of tumor initiation. To understand the role of PGCCs in chemoresistance, we monitored paclitaxel-induced PGCCs by conventional and live-cell fluorescence time-lapse recording. We found that paclitaxel induced massive cell death but also initiated endoreplication to form PGCCs. These PGCCs continued to grow via endoreplication, endomitosis, or cytofission before generating new mononuclear or multinucleated daughter cells via nuclear fragmentation or budding. These daughter cells resumed mitosis with a new stable karyotype and exhibited drug resistance. Budding from PGCCs was also observed in chemotherapy-treated ovarian cancer specimens from patients. On the basis of our findings, we propose the existence of an amitotic giant cell cycle composed of four phases: initiation, maintenance, termination, and speciation. We believe this is the first report of fluorescent live-cell imaging of the birth of resistant cancer cells at the single-cell level in response to paclitaxel treatment. Our findings provide strong evidence that a stress-induced amitotic giant cell cycle may be a programmed event underlying chemotherapy resistance and cancer relapse.